Preparation of hydroxy mercapto butyric acids and derivatives thereof



PREPARATION or HYDROXY MERCAPTO U? TYRIC ACIDS AND DERIVATIVES rnnnnoa Y Constantine E. Anagnostopoulos, Waltham, and Robert J. Wineman, Concord, Mass, assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Filed Oct 1, 1953, Ser. No. 333,694

1 Claim. ('Cl. 2 60- 53-s ,The present invention relates to novel hydroxy butyric acids containing mercapto groups, and to derivatives of such acids, and methods of preparing such compounds. More particularly. the invention relates to the preparation of alpha-hydroxy-gamma-mercapto butyric acid and derivatives thereof. v

It is a primary object of the invention to provide hydroxy mercapto butyric acid compounds, and derivatives thereof, which are highly useful as additives to. poultry feed compositions to promote growth or forthe purpose of increasing the eliective utilization of the feed by the poultry. e

Still further objects and advantages of the invention will become apparent from the following description and appended claim.

The preparation of the hydroxy mercapto butyric acids of the present invention can be exemplified by .theprocess of preparing alpha-hydroxy-gamma-mercapto butyric acid and its alkaline earth metal salts. The process is in general carried out by reacting hydrocyanic acidwith beta-acetylthiopropion-aldehyde in the presence of a basic catalyst. Preferably an excess of the hydr'ocyanic acid is added to the propionaldehyde in the presence of about 1% catalyst. The resulting cyanohydrin is treated directly with sulfuric acid, which hydrolyzes the cyanohydrin to the corresponding alpha-hydroxy acid and at the same time hydrolyzes the acetylthio grouping to form the corresponding free mercaptan and acetic acid.

Patented July 26, 1 960 of Hg is the gamma-thiolactoneof alpha-hydroxy-gammamereapto butyric. acid, 'whichhas the following formula:

omornomorr o If 'desired',.the-; neutralization fstepto piecipitate, the

J sulfate'ions'may'beoniitted, and insteaduthe acidic-hydrolysis fmixture may be cooled, preferably to; 2010-3-59 (3.; andthenextractedand distilled ashereinbeforede; scribed. *3}.

The corresponding :free' hydrox'y mercapto butytic acid is obtained from this lactoneby reacting it with a mineral The reaction mixture is then heated, preferablyat some temperature between 80-and 110 C., and finally neunesium hydroxide. which in the case of calcium hydroxide, is mostly calcium sulfate. After removing thepr ecipitate by filtration, the remaining clear filtrate-is evaporatedto a smaller volume (preferably a quarter or less of its original volume), and is then cooled to precipitate the calcium or other alkaline earth metal salt of the hydroxy mercapto butyric acid. When calcium hydroxide is used, this salt is the calcium salt of alpha-hydroxy-gammamercapto butyric acid, which is the calcium salt of the alpha-hydroxy analogue of homocysteine. The free alpha-hydroxy gamma-mercapto :butyric acid canbe obtained by a variation of the above procedure,

' in accordance with which the reaction mixture resulting from the hydrolysis with sulfuric acid, instead of being neutralized with an excess of calcium hydroxide'oi' other alkaline earth metal hydroxide is treatedwith a calculated amount of alkaline earth metal hydroxide or carbonate sufficient only to precipitate all the sulfate ions as the corresponding sulfate, which is filtered oif. The

and X and Y together represent S. v The salts so prepared arecrystalline solids, which are acid, extracting, with ether or other water-immiscible organic solvent, after which the solvent layer is separated 'and' the solvent ise'vaporated; The viscous liquid thus obtained is alpha-hydroxy-gamma-inercapto butyric acid.

' Alternatively the free hydroxy' mercapto butyric vacid can be prepared by hydrolyzing the. cyanohydrin of beta,- acetyl-thiopropionaldehyde with sulfuric acid'as hereinbefore described, extracting theresultingacidic hydrolysis mixture with a water-immiscible organic solvent, and

evaporating the solvent. e s :In' addition tothe calcium salt of thejabove .hydroxy mercapto .butyric'a'cid, it is also possible to;prepare the ammonium and: alkali metal salts including;.-for example the sodium and; potassium salts These, maybeprepared by careful neutralization of the acid, or solution of the acid, with. ammonia, or suitable alkali metal hydroxide. The various c'ompounds prepared as described above, and "otherwise forming a part'of this invention, maybe represented by the general formula: 1- r H H H 9 'O-'a lkaline earth metal soluble in hot water, but not soluble in the usual organic solvents. The free acidsare viscous liquids, whichcould not be obtained incrystalline'form. They are soluble.

in 'water, and in certain organic solvents, such as ethyl alcohol, diethyl ether, acetone afn d' 'other polar solvents. All of these'compourids are useful in poultry feeds' v vhen added in quantities between 0.005 and 1.0% by weight, based on the feed or ration, to promote the growth of the poultry and/or to improve the efiiciency of feed utilization by the poultry. The amounts employedjwithin this range are dependent on the particular poultry feed compositions used. They are also useful as intermediates in the preparation of other organic compounds.

A further understanding of the compoundsand processes of this invention will be obtained from the following examples, parts and percentages being by weight unless otherwise specified.

Example I was continued for an additional 30 minutes, after which time the excess of hydrocyanic acid was removed by the application of a pressure of 25 mm. of Hg. The resulting rcyanohydrin was directly hydrolyzed by the :slow addition of a mixture of 124grjams of (50110611: trated (97%) sulfuric acid and 92 ml. of water. The reaction mixture was kept at about 35 to 40 C. by external cooling. Sufficient water was then added to make a 20 to 25% I aqueous sulfuric acid solution which was thereupon heated at 80 C. for 2 hours. rFifty-five grams of zinc dust were then added for a period of 1 hour while maintaining the reaction mixture at about 75 C. This was done to reduce any dialkyl disul'fide that might have been formed to the free mercaptan.

The resulting solution was cooled to room tempera ture and 150 grams (1.5 mole) of calcium carbonate was added to precipitate all the sulfate ions present ascalcium sulfate. and the clear filtrate further diluted with 100 ml. of water and heated to about 52 C. A calcula'ted amount of culated on the basis of the formula (C H OgS) Ca;

C=30.95%, H=4.54'%, -S=20.-65'%, Ca=12.9 1% and O=30.95%. Found by analysis; C=30.9%, H=4.5%, S=20.6%, Ca=13.0% and O=31.0% (by difference).

Example II Preparation of the gamma-thiolactone of alpha-hydroxy-gamma-mercapto butyric acid.

The reactions were carried out as described in Example I for the preparation of the calcium alpha-hydroxygamma-mercapto butyrate up to the point where the precipitate was removed after the addition of calcium carbonate. The resulting clear filtrate was extracted with five portions of 250 ml. each of ether, and the ethereal layer was washed with 250 ml. of water and dried over sodium sulfate. Evaporation of the ether left an oily residue which was distilled under reduced pressure. The fraction boiling between 160 C. at a pressure of 27 mm. of Hg and 160 C. at apressure of 29 mm. of Hg was collected and identified as the gamma-thiolactone of alpha-hydroxy-gamma-mercapto butyric acid. Calculated 4 on the basis of the formula C H O S; C=40.65%, H=5.12%, S=27.14% and O=27.09%. Found by analysis; C=40.7%, H=5.3%, S=27.2% and O=26.8% (by difference).

Example 111 'Prepara-tionof alpha-hydroxy-gamma-mercapto b-utyric acid. The thiolactone prepared as described in Example II was converted to the tree 'alpha-hydroxy-gamma-mercapto butyric acid in the following manner. Ten grams of the thiolactone was placed in 100 ml. of 37% hydrochloric acid and warmed for five minutes on a steam :bath. The cooled,cl'e arsolution was'then extracted with three portions of 100 ml. each of ether and the combined ethereal solutions were dried over sodium sulfate. The

' ether was then removed under a reduced pressure of The resultingprecipitate was filtered ofl 1 mm. of Hg, leaving as residue the alpl1a-hydroxy-gamma mercapto butyric acid. The neutralization equivalent of the acid Was 142 (calculated neutralization equivalent: 136).. The calcium salt of the acid was prepared in the conventional manner, that is, by adding calcium hydroxide to an aqueous solution of the acid and evaporating to a small volume,- at which time the calcium salt precipitated out. a The calcium salt so prepared was identical with the calcium salt prepared as described in ExampleI by comparison of infrared spectra.

Whatis claimed is:

The method of preparing calcium alpha-hydroxygan1ma-mercapto butyrate which comprises reacting hydrocyanic acid with beta-acetylthiopropionaldehyde in the presence of a basic amine catalyst, hydrolyzing the resulting cyanohydrin with sulfuric acid, heating the reactionmixture at a temperature between and C., neutralizing it with an excess of calcium hydroxide, filtering 0H the precipitated calciunt sulfate, evaporating the filtrate to a volume not more than one-quarter its original volume, and allowing the solution to cool, whereby aprecipitate is formed.

Jacobson, J. A.C.S., 68: 21628 (1946).

Wagner and Zook: Synthetic Org. Chem., John Wiley and Sons (1953.).

Akobe et al.: Chem. Abstracts 31: 736 (1937).

Koelsch, J.A.C.S. 52: 1107 (1930). 

